Cost-effectiveness of managing HBV reactivation in patients with resolved HBV infection treated with anti-CD20 antibody for B-cell non-Hodgkin lymphoma

There is no universal recommendation for managing the reactivation of HBV in patients with resolved HBV infection treated with anti-CD20 monoclonal antibodies for B-cell non-Hodgkin lymphoma. This study compared the cost-effectiveness of two commonly used strategies: prophylactic anti-HBV nucleos(t)ide analog therapy (Pro NAT), and HBV DNA monitoring followed by on-demand antiviral therapy (HBV DNA monitoring). Using a decision tree model, the incremental cost-effectiveness ratio (ICER) expressed as cost per quality-adjusted life-year (QALY) gained was calculated. The threshold for cost-effectiveness was set at 5,000,000 JPY, equivalent to 45,662 USD. In a base–case analysis, HBV DNA monitoring was found to be more cost-effective based on the calculation of ICER as 132,048 USD per QALY, a value that far exceeds 45,662 USD. The same results were consistently obtained by a one-way deterministic sensitivity analysis, even after changing each parameter value within the predetermined range. A probabilistic sensitivity analysis with 10,000 simulations also revealed that HBV DNA monitoring is more cost-effective than Pro NAT in 96.8% of cases. Therefore, this study suggests that HBV DNA monitoring is an appropriate managing measure in Japan from a cost-effectiveness perspective.

Supplementary Method S1. Cost assumptions  Medical fees under the health insurance system in Japan in April 2020 were used.
 Patients were treated at the University of Tokyo Hospital.
 Patients visit the hospital every month to prevent HBV reactivation in both strategies.
 After the detection of reactivation, patients continue to visit the hospital every month.
 If hepatitis or fulminant hepatitis occurs, patients are hospitalized.
 Given the usual behavior of patients with lymphoma, patients do not receive outpatient treatment on weekends or in the evening.
 Entecavir (in the form of Entecavir tablets, a generic version of Baraclude tablets) is used as a nucleic acid analog (NA), as this drug is the cheapest and the most widely used in Japan.
 Screening tests for HBsAg, a hepatitis B core antibody, HBsAb, HBV-DNA quantification, ALT, and several biochemical tests are performed every visit, as shown in Supplementary Excel File S2.
 NA is provided by pharmacies in the "basic fee for dispensing one" category, in which 90% of pharmacies in Japan are categorized, and patients do not visit pharmacies on weekends or in the evening. However, if a patient is hospitalized, NA is provided by the hospital.
 Since patients have already received treatment for lymphoma before they visit the hospital to manage HBV reactivation, all visits are treated as re-examinations.
 Patients without reactivation receive either Pro NAT or HBV DNA monitoring for 18 months; this was assumed because most HBV reactivations occur within the 12 months after the end of chemotherapy 1-5 .
According to the Japanese Society of Hematology guideline for Tumors of Hematopoietic and Lymphoid Tissues 6 , 6-8 cycles of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) regimen were recommended for patients with diffuse large B-cell lymphoma, if not otherwise specified. Thus, in this study, we assumed that anti-CD20 antibodies treatment for lymphoma is given in eight cycles to patients (21 days × 8 cycles / 30 days ≈ 6 months). After 18 months, patients received no treatment (i.e., the cost is 0).
 For patients with HBV reactivation, NA treatment is provided over 24 months. After that, no treatment is provided (i.e., the cost is 0).
 Treatments for hepatitis and fulminant hepatitis were performed under hospitalization management.
 If hepatitis and/or fulminant hepatitis occurs and is resolved, NA treatment is provided over 24 months after discharge from the hospital. The treatment is the same as that for HBV reactivation.
 If fulminant hepatitis does not develop after acute hepatitis, then the diagnostic procedure combination (DPC) payment is applied for the first month, and piecework payment is applied thereafter under the health insurance system of Japan.
 If fulminant hepatitis is developed after acute hepatitis, DPC payment is applied for the first and second months, and piecework payment is applied thereafter.  The utility value determined by medical specialists using EQ-5D-5L.
Range is set at 20% of variation.
Lower range is set at 20% variation and upper range is set at 0. HBV DNA levels fall below the detection limit within one or two months by antiviral therapy.
Japanese yen was converted into US dollars using the exchange rate on July 20, 2021: USD 1 = JPY 109.5.